Thymic stromal lymphopoietin (TSLP) is a cytokine derived from epithelium cells, which is produced in response to pro-inflammatory stimuli. Mainly, TSLP enhances an allergic inflammatory response through the activation of dendritic cells and mast cells. The dendritic cells express TSLP receptor and IL-7 receptor α-chain which are members of a hematopoietic receptor family, and TSLP binds to a heterodimer consisting of TSLP receptor and IL-7 receptor α chain, thereby activating the dendritic cells. The dendritic cells activated by TSLP express inflammatory chemokines such as thymus and activation regulated chemokines (TARC (CCL17)), macrophage-derived chemokines (MDC (CCL22)), and the like (Nat. Immunol., 2002, Vol. 7, p. 673 to 680). It has been known that TARC and MDC are Th2 chemokines and attract Th2 cells to an inflammation site (Int. Immunol., 1999, Vol. 11, p. 81 to 88). Further, the dendritic cells activated by TSLP strongly induce the differentiation of naïve T cells into Th2 cells, and the Th2 cells produce IL-4, IL-5, IL-13, and TNFα, and cause the inflammatory reaction (Nat. Immunol., 2002, Vol. 7, p. 673 to 680).
It has been reported that the activation of the dendritic cells due to TSLP through such TSLP receptor is involved with disease pathology, including allergic inflammatory diseases such as asthma, and systemic sclerosis.
With regard to asthma, it has been reported that in transgenic mice in which the TSLP expression is enhanced specifically in a lung, the inflammatory response in an airway is caused accompanied by an increase of the amount of IgE and the Th2 cytokines in a lung, and this leads to asthmatic pathology (Nat. Immunol., 2005, Vol. 6, p. 1047 to 1053). Further, in knockout mice of TSLP receptor or an asthma model to which an anti-TSLP receptor antibody is administered, the suppression of Th2 cytokines and IgE production in the blood, and the improvement of respiratory function have been observed (J. Exp. Med., 2005, Vol. 202, p. 829 to 839, and Clin. Immunol., 2008, Vol. 129. p. 202 to 210). In addition, in asthma patients, it has been reported that expressions of TSLP, TARC, and MDC increases in the asthmatic airways in correlation with the severity of the disease (J. Immunol., 2005, Vol. 174, p. 8183 to 8190, and J. Immunol., 2008, Vol. 181, p. 2790 to 2798).
With respect to systemic sclerosis, it has been reported that TSLP is overexpressed in the skin of systemic sclerosis patients (Arthritis Rheum., 2013, Vol. 65, p. 1335 to 1346), and that expression of IL-13 and IL-17 in inflammation site of skin is almost completely suppressed and the proportion of collagen to histopathology was significantly improved in a bleomycin-induced scleroderma model using TSLP receptor-knockout mice (Ann. Rheum. Dis., 2013, Vol. 72, p. 2018 to 2023).
Accordingly, when a monoclonal antibody that specifically binds to human TSLP receptor and inhibits an action of human TSLP through human TSLP receptor can be developed, it is expected that such antibody is useful for preventing and treating various diseases in which human TSLP and human TSLP receptor are involved in disease pathology.
As antibodies against human TSLP receptor for which research has been conducted so far, 13H5 as a mouse monoclonal antibody and hu13H5 as a humanized antibody thereof (Patent Document 1), 1D6.C9 as a mouse monoclonal antibody and Nv115-3B-IgG1 and NV115-3B-IgG4 as chimeric antibodies thereof (Patent Document 2), NV164-1 and NV163-1 as fully human antibodies (Patent Document 3), and TSLPR-012_141 as a humanized monoclonal antibody derived from a hamster have been reported.
In 13H5, neutralizing activity has been confirmed in a TSLP-induced proliferation assay using Ba/F3 cells stably expressing human TSLP receptor, but neutralizing activity in hu13H5 has not been confirmed yet (Patent Document 1). Further, based on description of Patent Documents 2 to 4, among the antibodies described in these documents, it is recognized that TSLPR-012_141 has the highest neutralizing activity (Patent Documents 2 to 4). TSLPR-012_141 has been evaluated through various tests of neutralizing activity. For example, in the TSLP-induced proliferation assay using Ba/F3 cells stably expressing human TSLP receptor, TSLP-induced TARC, MDC, and IL-8 production assay using human peripheral blood-derived dendritic cells, TSLP-induced Th2 cytokine production assay using human peripheral blood-derived dendritic cells and naïve T cell co-culture systems, and the like, TSLPR-012_141 has been confirmed to show the neutralizing activity (Patent Document 4). However, an antibody showing high neutralizing activity for being used as antibody drug is desirable.
The main factors that determine the effective dosage of an antibody drug include binding activity and neutralizing activity of the antibody against an antigen as well as an amount of the antigen which is present in the body. An increase of the binding activity and neutralizing activity leads to reduction in dosage, and as a result, leads to reduction in financial burden and medical expenses of patients, which is an extremely beneficial improvement.
Therefore, it is necessary to obtain an anti-human TSLP receptor antibody which is excellent in activity compared to the conventional anti-human TSLP receptor antibody to be used for preventing and treating various diseases.